MXPA06011830A - Pharmaceutical composition comprising a salt of mirtazapine. - Google Patents

Abstract

The invention provides for a pharmaceutically suitable non-sublimating and solid salt of an enantiomer of mirtazapine, in particular, a mirtazapine salt selected from the list of the salt of maleic acid, hydrobromic acid and fumaric acid, for use in the manufacture of a pharmaceutical composition comprising a salt of S- or R-mirtazapine.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A MIRTAZAPINE SALT The invention relates to pharmaceutical formulations comprising a pure enantiomer of mirtazapine. Mirtazapine is a widely used drug with various therapeutic uses. The form of the drug that is available in pharmaceutical compositions for prescription to patients is the base of the compound as a racemic mixture. In view of the new uses of the drug and the different pharmacological properties of the enantiomers, it is necessary to make available separately the S- and R-enantiomers for the pharmaceutical compositions. Pharmaceutical compositions for oral use of enantiomers were implied to be available according to the publication of Fink and Irwin (Psychopharmacology, Vol. 78, pp. 44-48, 1982) who describe the administration of the S-enantiomer and the R-enantiomer of mirtazapine in human volunteers for research purposes. The compounds were given in the form of the free base of an S- or R-enantiomer of mirtazapine. It was found that such formulations suffer from problems caused by the sublimation of mirtazapine. It was found that the pure bases of S- and R-mirtazapine are compounds of slow sublimation at room temperature and that some, but not all salts of S- and R-mirtazapine, do not have this disadvantage. Therefore, the utility of such a pharmaceutical composition comprising an enantiomer of mirtazapine in solid form, according to this invention, can be improved by selecting a non-sublimated, pharmaceutically suitable and solid salt of an enantiomer of mirtazapine in the composition. The invention also provides a method for the manufacture of a pharmaceutical formulation comprising a pure enantiomer of mirtazapine in a solid form, whereby the solid form is a non-sublimated, pharmaceutically suitable salt of S- or R-mirtazapine. Other desirable properties for a pharmaceutical ingredient, such as easy preparation or purification or chemical or physical stability in capsules and / or tablets, may also be obtained by the use of a salt according to this invention. The improved physical stability may be due to reduced migration of the compound out of the formulation and the improved chemical stability may be due to reduced degradation of mirtazapine. The non-sublimated and solid salts of S-mirtazapine as well as of R-mirtazapine are found to be a. or. the salts of maleic acid, hydrochloric acid, hydrobromic acid, fumaric acid and methanesulfonic acid. The maleic acid salt is particularly advantageous, because it has a high melting point, forms crystals easily, for which no other polymorphs are formed and is not hygroscopic. Also, the methanesulfonic acid salt is a very useful salt for an enantiomer of mirtazapine, in view of nil sublimation and hygroscopicity. A trifluoroacetic acid salt of S- or R-mirtazapine is an example of a salt that showed sublimation. In addition, the last salt is not a pharmaceutically suitable salt. The property of sublimation can be observed and quantified by known methods for measuring sublimation. For example, sublimation can be measured in an apparatus with a chamber in which the test compound is placed in its solid state and maintained in that state by controlled temperature. The gel phase in the chamber, optionally under low pressure, can be analyzed with respect to the content of the test compound. It is also possible to continuously clean the test compound in the gas phase from the chamber either by a continuous gas renewal stream or by creating a well for the test compound outside the gas phase, for example, by a cold surface. The amount of material collected from sublimation or that escapes from the sample by sublimation can be analyzed. The degree of sublimation is expressed as the fraction (as a percentage) of the initial sample size. The term 'salt without sublimation' is defined as a salt of S- or R-mirtazapine, from which less than 1% of the mirtazapine is sublimated from the sample, calculated on the basis of the amount of the base, when a sample of about 10 mg (for example, an amount between 8-12 mg) it is placed for the duration of 72 hours under standard conditions of 1 50 mBar pressure and 60 ° C temperature. The pharmaceutically suitable acids, approved for use in order to provide the anion in a salt of a medicinally active compound, are hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid, methylsulfonic acid, acetic acid and other acids mentioned in article by Philip L. Gould (International Journal of Pharmaceutics, Vol. 33, (1986), pp. 201-207.) This publication provides the limitation and definite list of acids, which can be examined according to procedures prescribed in this description in order of obtaining a salt according to the invention The term 'solid' in this description means that the amorphic or crystalline compound remains in a solid state at room temperature The term mirtazapine refers to compound 1, 2,3,4,10 , 14b-hexahydro-2-methyl-pyrazino [2, 1-a] pyrido [2, 3-c] [2] benzazepine as an active ingredient for a pharmaceutical formulation. Here, reference is made to the free base as a separate compound or to the base component in a mirtazapine salt. The reference to a formulation comprising an enantiomer of mirtazapine refers to a formulation in which an enantiomerically purified form of mirtazapine was used in the preparation, as opposed to a formulation for which the racemic form of mirtazapine was used. The purification in this paragraph is understood to involve one or more steps in the preparation of mirtazapine, which are required in obtaining a certain degree of separation of the two enantiomers. Preferably, a pure enantiomer of 90%, or preferably better of up to 95%, 98%, 99%, 99.5% or 99.8% purity is used over the other enantiomer. Mirtazapine, 1, 2,3,4, 10, 14b-hexahydro-2-methyl-pyrazino [2, 1-a] pyrido [2, 1-a] pyrido [2,3-c] [2] benzazepine, it can be prepared by known methods. The synthesis of racemic mirtazapine is described, for example, in US4062848, where a synthetic four-step scheme starting from 2-substituted nicotinitrile is set forth. Further modifications to various steps of this route have been described subsequently in WO 00/62782, WO 01/23345 and EU 6,376,668. The preparation of enantiomerically pure mirtazapine has been directed in EU 4062848, WO 00/62782 and Selditz et al. , 1998 (J. Chromatography, 1 998, vol 803, pp 1 69-177). By the method set forth in US 4062848, the enantiomerically pure mirtazapine is obtained by fractional crystallization of the diastereoisomeric salts formed by reaction of racemic mirtazapine with enantiomerically pure dibenzoyltartaric acid in ethanol, followed by regeneration of the free base by treatment with aqueous ammonia. Other methods of pure mirtazapine formation by recrystallization of pure mirtazapine are disclosed in WO 00/62782. Selditz et al. , describes a chromatographic method for separating the enantiomers. The pharmaceutical compositions are made with an active ingredient, which is an S- or R-mirtazapine salt in this context, to which vehicles and other excipients are added. The characteristics of the salts according to the invention make them more suitable for manufacture and use in various pharmaceutical formulations for dosed administration to a subject. Such forms are adapted for use in particular routes of administration, such as oral, rectal or transdermal. For the preparation of dosage forms, such as pills, tablets, suppositories, (micro) -capsules, powders, emulsions, creams, ointments, a patch, a gel, or any other preparation for prolonged release, sprays, injection preparations in the form of a suspension, suitable auxiliaries such as fillers, binders, lubricants, dispersants, emulsifiers, stabilizers, surfactants, penetration enhancers, antioxidants, dyes, preservatives and the like, can be used, for example, as described in the standard reference, Gennaro et al. , Remington; The Science and Practice of Pharmacy; 20th ed. , Publisher: Lippincott Williams% Wilkins; Baltimore; USA in Part 5) and the Pharmaceutical Excipients Manual (3rd Edition edited by Arthur H. Kibbe, Published by the American Pharmaceutical Association, Washington, D.C. and The Pharmaceutical Press, London in 2000). In general, any pharmaceutical auxiliary that does not interfere with the function of the active compound can be used and is suitable. The amount of S- or R-mirtazapine salt in the dosage form can be adapted to the particular circumstances. In general, a dose unit will contain between 0.05 and 90 mg of S- or R-mirtazapine salt, expressed on the basis of the amount of base.

Suitable fillers or vehicles with which the compositions can be administered include agar, alcohol, fats, lactose, starch, cellulose derivatives, polysaccharides, polyvinyl pyrrolidone, silica, sterile saline and the like, or mixtures thereof, used in adequate amounts. Binders are agents used to impart cohesive properties to a pharmaceutical composition, resulting in minimal loss of the pharmaceutical composition during production and handling. The binders are, for example, cellulose, starches, polyvinyl pyrrolidone and the like. A suitable lubricant with which the active agent of the invention can be administered is, for example, magnesium stearate.

Surfactants are agents that facilitate the contact and migration of compounds in different physical environments, such as hydrophilic and hydrophobic environments. Many surfactants are known in the art of preparing pharmaceutical compositions as described, for example, in chapter 21 of Gennaro et al. , Remington; The Science and Practice of Pharmacy; 20th ed. , Publisher: Lippincott Williams & Wilkins; Baltimore; USA). The surfactants that can be used during the preparation process of the pharmaceutical formulation are, for example, polyethylene glycol (PEG) and the like.

The salts according to the invention can be prepared by methods well known in the art. The base is dissolved in a suitable solvent, such as methanol, ethanol, ethyl acetate or acetone and acid is added either purely or dissolved in, for example, ethanol, ethyl acetate or acetone. Salt can be collected from the solvents by precipitation or crystallization, which, if needed, is caused by cooling the solution or evaporating the solvent.

Figure: Schematic presentation of the sublimation test equipment. A sample is placed in the bottom of a container, which is closed at the top by a shutter in the form of a container in which circulates the cooling liquid (CL) and whose container has an outlet connected to a vacuum pump (Vac). The container is placed in a closed chamber under constant temperature control (TC). A sublimate (Up) can accumulate against the surface of the shutter inside the container.

Examples In the examples S-mirtazapine is used. In view of symmetry, these can be copied directly to apply R-mirtazapine as well, except for Example 8, in which case (-) - O, O-dibenzoyl-L-tartaric acid should be used for R-mirtazapine. 1 . Crystallization of S-mirtazapine hydrochloric acid salt To a solution of 3.01 g of S-mirtazapine in 5 ml of ethanol was added at room temperature a solution of 939 μl of hydrochloric acid in 20 ml of ethyl acetate. Part of the solvent evaporated and oil formed in the solution. Then the solution was cooled to 0 ° C. A crystal was added in seed after which the crystallization began. The white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 1.96 g of white crystals of hydrochloric acid salt of S-mirtazapine (57%). The endothermic peak (DSC): 275 ° C; XRPD and ss-NMR: crystalline material of a polymorphic form, not amorphous material. The compound begins to sublimate above 170 ° C. The dynamic vapor sorption measurement showed that the salt is very hygroscopic. 2. Crystallization of maleic acid salt of S-mirtazapine To a solution of 3.01 g of S-mirtazapine in 10 ml of ethanol was added at room temperature a solution of 1.32 g of maleic acid in 10 ml of ethanol. After stirring for several minutes, crystallization began. After stirring several hours at room temperature, the white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 3.98 g of white crystals of maleic acid salt of S-mirtazapine (92%). The endothermic peak (DSC): 206 ° C; XRPD and ss-NMR: crystalline material, ratio mirtazapine: maleic acid: 1: 1; a polymorphic form, not amorphous material. The dynamic vapor sorption measurement showed that the salt is not hygroscopic. 3. Crystallization of fumaric acid salt of S-mirtazapine To a solution of 3.01 g of S-mirtazapine in 5 ml of ethanol was added at room temperature a solution of 1.31 g of fumaric acid resulting in rapid precipitation. An additional 5 ml of methanol and 20 ml of ethyl acetate were added to the suspension in order to re-dissolve the solid. Part of the solvent was evaporated to initiate crystallization from a clear solution. After stirring for several hours, the white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 3.76 g of white crystals of S-mirtazapine fumaric acid salt (87%). The endothermic peak (DSC): 178 ° C; XRPD and ss-NMR: probably a mixture of three polymorphic forms and some amorphous material. The fumaric acid salt attracts water from the ambient air to form a hydrate, which loses its water content after drying. 4. Crystallization of hydrobromic acid salt of S-mirtazapine To a solution of 3.01 g of S-m irtazapine in 5 ml of ethanol was added at room temperature a solution of 1290 μl of hydrobromic acid in 20 ml of ethyl acetate. Part of the solvent evaporated, which resulted in the formation of an oil. The mixture was cooled to 0 ° C after which crystallization was initiated. The white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 3.74 g of white crystals of S-mirtazapine hydrobromide salt (95%).

The endothermic peak (DSC): 253 ° C; XRPD and ss-NMR: mainly a polymorphic form and some amorphous material. The HBr salt has a clear affinity for water and forms a monohydrate under ambient conditions. A sample of water-free drug substance attracts water when it comes in contact with ambient air, while losing water after drying. 5. Crystallization of methanesulfonic acid salt of S-mirtazapine To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol was added at room temperature a solution of 743 μl of methanesulfonic acid in 20 ml of ethyl acetate. After partial evaporation of the solvent, crystallization began. The white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 2.09 g of white crystals of methanesulfonic acid salt of S-mirtazapine (51%). The endothermic peak (DSC): 208 ° C; XRPD and ss-NMR: crystalline material mainly a polymorph. 6. Crystallization of trifluoroacetic acid salt of S-mirtazapine To a solution of 0.50 g of S-mirtazapine in ethyl acetate was added a solution of 142 μl of trifluoroacetic acid in ethyl acetate. As the crystallization did not start spontaneously, the solvent slowly evaporated. During the evaporation of the solvent, the salt began to crystallize. This produced 0.65 g of trifluoroacetic acid salt of S-mirtazapine. The endothermic peak: 1 85 ° C. In the I experiments according to Example 10, it was found that this salt was not a salt without sublimation according to the definition of a salt without sublimation in this description. 7. The solidification of S-mirtazapine formic acid salt, S-mirtazapine acetic acid salt, S-mirtazapine propionic acid salt and S-mirtazapine phosphoric acid salt was not successful. Example 8. This is to demonstrate the first step in an enantiomerically pure manner of preparing mirtazapine. The salt in this example is not approved for pharmaceutical use. Crystallization of salt of S-mirtazapine (+) - Q, Q-Dibenzoyl-D-Tartaric acid 23.33 g of mirtazapine (Org 3770) were dissolved in 94 ml of ethanol at a temperature of 52 ° C. A filtered solution of 33.06 g of (+) - O, O-dibenzoyl-D-tartaric acid hydrate in 32 ml of ethanol (100%) was added to the warm solution. Then, the reaction mixture is warmed to room temperature. A crystal seed was added to the reaction mixture to initiate crystallization. After stirring for 1 9 hours, the crystals were collected by filtration. The production of the wet crystals was 25.7 g and the e.e. it was 88.04%. The crystals were suspended in 880 ml of ethanol and dissolved at reflux temperature. The reaction mixture was warmed and crystallization initiated. After 16 hours, the crystals were collected by filtration. The yield of the wet crystals was 20.4 g and the e.e. It was 98.9%. The remaining mother liquor can be used to obtain R-mirtazapine by combining it with (-) - O, O-Dibenzoyl-L-Tartaric Acid. 9. Assay for S-mirtazapine and degradation products by HPLC Column ODS Hypersil, 250 x 4.6 mm ID, 5 μm or equivalent column Column temperature 40 ° C Solution A Methanol + acetonitrile + tetrahydrofuran, 36.2 + 42.5 + 21 .3 , V + V + V Mobile phase Solution A + 0.1 M tetramethylammonium hydroxide pentahydrate solution (pH = 7.4), 35 + 65, V + V Flow rate 1 .5 mL / min Detection S-mirtazapine: UV 290 nm Prod Degr A: UV 240 nm Prod Degr B: UV 240 nm Prod Degr C: UV 240 nm Prod Degr D: UV 240 nm I njection volume 1 0 μL Execution time 27 minutes Approx. Retention times * S-mirtazapine 14.5 < Tr < 17.5 minutes Prod Degr A 23.1 minutes Prod Degr B 3.0 minutes Prod Degr C 5.6 minutes Prod Degr D 3.7 minutes * If the retention time of the S-mirtazapine peak does not conform to the system adequacy criteria before analysis, the mobile phase should be adjusted by adding some of solution A or 0.1 M of tetramethylammonium hydroxide pentahydrate solution .The detection limit of S-mirtazapine as a free base or as an active entity in its corresponding salt is below 0.02 mg. Names: Prod Degr A: 2,3,4,4a-Tetrahydro-3-methylpyrazino [2, 1-a] pyrido [2, 3-c] [2] benzazepine-9 (1 H) -one Prod Degr B: Dihydrate of 1, 2, 3,4, 10, 14b-Hexahydro-2-methylpyrazino [2, 1-a] pyrido [2,3-c] [2] benzazepine-2-oxide Prod. Degr. C: 3,4, 10, 14b-Tetrahydro-2-methylpyrazino [2, 1-a] pyrido [2,3-c] [2] benzazepin-1 (2H) -one Prod Degr D: N- [2- (5, 10-dihydro-10-oxo-1 1 H -pyrido [2,3-c] [2] benzazepin-1 1 -i I) ethyl] -N-methyl-f ormamide 10. Sublimation tests One sample (approximately 10 mg) was placed in a sample chamber of the sublimation test kit, as illustrated in Figure 1. The temperature in the sample chamber is controllable. The sample holder has a reduced pressure, which can be 150 mBar by default. The sample chamber also consists of a section with reduced temperature (the "cold claw"), where the temperature is about 5 ° C. The majority of the sublimated material in the test sample with high temperature will precipitate in the cold claw. The amount of material in the cold claw after a 72-hour test period has been quantified by the use of HPLC analysis. The degree of sublimation is expressed as the fraction material in the cold claw (as a percentage) of the initial sample size. Additionally, the sublimation of the active compound from "drug product" into tablets has been examined. Results Table 1 lists the sublimation results of S-mirtazapine, S-mirtazapine. HBr, S-mirtazapine. maleic acid, S-mirtazapine. fumaric acid and tablets that contain some of these compounds under various test conditions. Table 1: Results of Sublimation Temper: 40 ° C Sublimate Drug Substance3 Pressure: 150 m bar S-mirtazapine Lot E 0.75% Test period: 72 hr S-mirtazapine Lot J 0.88% Temperature: 60 ° C Drug Substance Pressure: 150 m bar S -mirtazapina Lot E 5.32%, 2.22% Trial period: 72 hrs S-mirtazapina Lot J 4.29% S-mirtazapine. H Br < DL S-mirtazapine. maleic acid < DL S-mirtazapine. fumaric acid < DL S-mirtazapine. HCl 0.2% 0.2% S-mirtazapine. 0.1% methanesulfonic acid, 0.0% Drug Product (tablets1, Tablets S-mirtazapine 7.21% Tablets S-mirtazapine HBr < DL Tablets S-mirtazapine, maleic acid1 < DL < DL = Below the level of detection a If two values are mentioned these are results of reproduction experiments 1 The composition of the tablets used for the sublimation test detailed in table 3. Formulation C as in table 3.

Table 2: Stability results Table 2 Continuation A = environmental humidity RH = relative humidity 1 All tablets, except some of the S-mirtazapine tablets. Maleic acid salt, contain approximately 1 mg of S-mirtazapine calculated on the basis of the amount of the base.

However, due to losses during the manufacturing process, the content may be lower. The formulations are shown in table 3. 2 The first row shows the results of the 1 mg / 65 mg tablets (formulation F, see table 3). The second row shows the results of the tablets of 10 mg / 160 mg (formulation G, see table 3). Table 3: Composition of the tablets Table 3 Continuation Notes for Table 3 1 Due to losses or other problems during the manufacturing process, the content may be lower or higher. 2 Corresponds to 1 mg of S-mirtazapine as a base. 3 Corresponds to 10 mg S-mirtazapine as a base.

The results of the sublimation test show that the free base S-mirtazapine is sublimated under the conditions used. The hydrobromic acid salt of S-mirtazapine, the maleic acid salt of S-mirtazapine and the fumaric acid salt of S-mirtazapine are not sublimed. This difference is also observed in tablets containing S-mirtazapine, S-mirtazapine. HBr or S-mirtazapine. maleic acid. The stability of the tablets containing S-mirtazapine and S-mirtazapine. Maleic acid was also measured (tables 2 and 4). It is clear that the content of S-mirtazapine decreases in the tablets containing the free base S-mirtazapine. The decrease is probably caused by sublimation. In the tablets that contain S-mirtazapine. Maleic acid no decrease in content was observed. The chemical stability of the drug products was further analyzed by determination of the chemical degradation products. The test values after storage are shown in Table 4. Table 4: Stability and degradation products test Notes for Table 4 1 All tablets contain approximately 1 mg of active substance (S-mirtazapine). However, due to losses during the manufacturing process, the active entity content may be lower. The formulations are shown in table 3. n.d. = not determined A = environmental humidity Note that in tablets containing S-mirtazapine. Maleic acid no decrease in content was observed. The degradation products found in the tablets containing S-mirtazapine or S-mirtazapine. Maleic acid are provided in Table 4. The formulation of the tablets is similar (Table 3). In the tablets that contain S-mirtazapine. maleic acid stored for 3 months at 40a / 75% RH, the concentration of the degradation products was lower than in the free-containing S-mirtazapine-containing tablets that were stored during the same period. The losses under conditions of 60 ° C at room temperature were not too much for the maleic acid salt while for the free base formulation, the degradation products already amounted to about 1 1%.

Claims (5)

1. CLAIMS 1. A pharmaceutical formulation comprising an enantiomer of mirtazapine, characterized in that mirtazapine is presented as a pharmaceutically suitable non-sublimated mirtazapine solid salt.
2. 2. The pharmaceutical formulation according to claim 1, characterized in that the salt is selected from the list consisting of the salt of maleic acid, hydrobromic acid, fumaric acid and methanesulfonic acid.
3. 3. The pharmaceutical formulation according to claim 2, characterized in that the salt is of maleic acid or methanesulfonic acid.
4. 4. The salt of the pharmaceutical formulation according to any of claims 1 -3, characterized in that the enantiomer of mirtazapine is the S-enantiomer.
5. 5. A method for the manufacture of a pharmaceutical formulation comprising an enantiomer of mirtazapine in a solid form, characterized in that the solid form is a non-sublimated, pharmaceutically suitable salt of S- or R-mirtazapine.